TNF-α is one of the cytokines secreted from macrophages, monocytes and the like activated by exogenous and endogenous factors. TNF-α is extensively involved in promoting the secretion of various cytokines and in protecting against infection. However, the persistent and excessive production and secretion of TNF-α cause overproduction of inflammatory cytokines, apoptosis of cells, and interference of intracellular signal transduction and the like, resulting in the primary and secondary tissue damage, and eventually becomes a factor responsible for etiology and exacerbation of various disorders (see Non-Patent Literature 1). Therefore, to treat a pathological condition thought to be caused by the excessive production and secretion of TNF-α, it is important to suppress the production and secretion of TNF-α, or to suppress the action of TNF-α. Examples of such diseases in which TNF-α participate include rheumatoid arthritis, systemic lupus erythematosus (SLE), Crohn's disease, Behcet's disease, multiple sclerosis, arteriosclerosis, myasthenia gravis, diabetes, sepsis, acute infectious diseases, asthma, atopic dermatitis, contact dermatitis, psoriasis, acne, fever, anemia and the like.
Tumor necrosis factor alpha converting enzyme (TACE) (also called ADAM 17), which is classified in the ADAM (a disintegrin and metalloproteinase) family, is a membrane-bound protease having zinc at a catalytic site thereof and TACE produces soluble TNF-α by cleaving membrane-bound TNF-α (pro-TNF-α). Therefore, compounds that inhibit the enzyme action of TACE are likely to suppress the production of soluble TNF-α, thereby serving as a therapeutic agent for the above-described various disease conditions caused by TNF-α. Based on this, research into compounds having a TACE inhibitory effect is being actively carried out (see Non-Patent Literature 2 and 3).
On the other hand, matrix metalloproteinase (also called matrixin) (MMP) is a protease having zinc at a catalytic site thereof and has an effect of degrading the extracellular matrix. Approximately 20 subtypes of MMP are known.
A compound that inhibits certain types of MMP has been reported as inhibiting the production of TNF-α as well (see Non-Patent Literature 4). Further, since TACE and MMP are both enzymes having zinc at a catalytic site and also have a similar three-dimensional structure, compounds that inhibit both MMP and TACE have also been reported (see Non-Patent Literature 5). However, it has been reported that rats continuously administered with an agent which inhibits many kinds of MMPs at the same time had a hypertrophic degeneration on the cartilage growth plates (see Non-Patent Literature 6), and that MT1-MMP (MMP-14) knockout mice were observed to present a symptom of arthritis (see Non-Patent Literature 7). There are concerns about the various side-effects that occur due to MMP inhibition based on these reports. In addition, since most of MMPs are involved in the maintenance and homeostasis of the extracellular matrix, which form the basic structure of a living body, inhibiting the catalytic activities of many MMPs nonselectively is likely to cause serious adverse effects on the living body. Therefore, it is preferred that a compound directed to TNF-α production inhibition based on TACE inhibition does not essentially exhibit an inhibitory effect against MMPs.
Patent Literature 1, Non-Patent Literature 8 and Non-Patent Literature 9 contain reports about compounds that selectively inhibit TACE. Further, Patent Literature 2 to Patent Literature 10 contain reports about TACE inhibitor compounds that have a hydantoin structure.